ABSTRACT The United States has experienced a dramatic rise in non-medical use of prescription opioids leading to increased demand for effective treatments for opioid use disorders. Recent evidence suggests that inactivation of Substance P receptors, either through genetic deletion or pharmacological blockade, significantly attenuates the rewarding effects of opioids in an array of laboratory models and suppresses expression of opioid withdrawal signs. Neurokinin 1 (NK1) receptors for Substance P may offer an attractive novel target for a non-addictive treatment approach. This project proposes two inpatient laboratory studies that will enroll individuals with opioid use disorders. These studies will provide the proof-of-concept evidence of NK1 receptor system involvement in mediating the response to opioids as related to abuse potential, reinforcing efficacy and opioid withdrawal in humans. These randomized, placebo-controlled, double-blind, inpatient studies will both employ a within-subject design and enroll otherwise healthy volunteers with current non-medical opioid use with (Exp. 1) and without (Exp. 2) physical dependence on opioids. Both studies will capitalize on the availability of a novel brain-penetrant NK-1 antagonist, VLY-686, for which requisite clinical safety data are available, and the sponsor (Vanda) has agreed to provide support and clinical drug supply. Experiment 1 will examine the effects of maintenance on VLY-686 (100 mg/day) versus placebo on opioid responses with oxycodone on an array of physiological, subjective and behavioral outcomes (self- administration and experimental pain). Experiment 2 will enroll opioid dependent volunteers who will be maintained on oxycodone throughout the study using an established procedure. This study will examine the effects of maintenance on VLY-686 (0 and 100 mg/day) for its ability to attenuate expression of opioid withdrawal signs and symptoms and to attenuate the response to opioid agonist challenge. These studies will provide preliminary safety and key pharmacodynamic data in individuals with opioid use disorders, both with and without physical dependence, and provide proof-of- concept data for the NK-1 receptor system role in mediating critical factors in opioid use disorders.